GABA B receptors (GABA BRs) mediate slow inhibitory effects on neuronal excitability and synaptic transmission in the brain. However, the GABA BR agonist baclofen can also promote excitability and ...seizure generation in human patients and animals models. Here we show that baclofen has concentration-dependent effects on the hippocampal network in a mouse model of mesial temporal lobe epilepsy. Application of baclofen at a high dose (10 mg/kg i.p.) reduced the power of γ oscillations and the frequency of pathological discharges in the Cornu Ammonis area 3 (CA3) area of freely moving epileptic mice. Unexpectedly, at a lower dose (1 mg/kg), baclofen markedly increased γ activity accompanied by a higher incidence of pathological discharges. Intracellular recordings from CA3 pyramidal cells in vitro further revealed that, although at a high concentration (10 µM), baclofen invariably resulted in hyperpolarization, at low concentrations (0.5 µM), the drug had divergent effects, producing depolarization and an increase in firing frequency in epileptic but not control mice. These excitatory effects were mediated by the selective muting of inhibitory cholecystokinin-positive basket cells (CCK ⁺ BCs), through enhanced inhibition of GABA release via presynaptic GABA BRs. We conclude that cell type–specific up-regulation of GABA BR-mediated autoinhibition in CCK ⁺ BCs promotes aberrant high frequency oscillations and hyperexcitability in hippocampal networks of chronic epileptic mice.
During field surveys conducted from July to October 2018–2020 in the eastern part of Georgia (Caucasus region), 145 out of 8000 (1.8%) and 147 out of 6600 (2.2%) grapevine plants, respectively, from ...mother stock/collection fields and commercial vineyards, were found exhibiting typical or suspicious grapevine yellows (GY) symptoms. Most of the symptomatic grapevine plants of Georgian cultivars showed mild symptoms with no berry alterations. Leaf samples from symptomatic plants were analyzed by serological (DAS- -ELISA) and molecular (two previously published protocols of TaqMan triplex real-time PCR, here named Set I and Set II) tools for detecting GY-associated phytoplasmas. The presence of GY phytoplasmas was not detected in any examined grapevines by a serological method. GY phytoplasmas were identified in 22.41% and 6.9% symptomatic plants from mother stock and collection vineyards and in 48.3 and 19.0% symptomatic plants from commercial vineyards by Set I and Set II PCRs, respectively. As expected from previous studies reporting the wide presence of bois noir (BN) in Georgian vineyards, ‘Candidatus Phytoplasma solani’(CaPsol) was detected in most phytoplasma-infected plants (47.6%), with the highest infection rate in Chardonnay. Phytoplasmas belonging to taxonomic group 16SrV were detected in 45.6% of the phytoplasma-infected grapevines. To the best of our knowledge, this is the first report of 16SrV phytoplasmas in Georgia and in the Caucasus region. Further molecular typing of 16SrV phytoplasma strains is necessary to determine if such strains are associated with flavescence dorée (FD). The knowledge of typical GY symptoms and the utilization of accurate diagnostic tools are crucial for preventing pathogen spread and producing healthy planting material. Based on the results obtained in this study, the presence of BN and 16SrV phytoplasmas should be monitored in the next years using triplex real-time PCR.
Abstract The phencyclidine compound MK-801 can induce psychosis with symptoms which closely resemble those observed in an acute schizophrenic episode. Here we used an in vitro model of psychosis ...after systemic administration of MK-801. We found that kainate-induced gamma frequency field oscillations in animals previously exposed to MK-801 have significantly higher power than in control animals. The intrinsic membrane properties of pyramidal cells, such as membrane input resistance and time constant, were not found to be different. In contrast, the MK-801 cells exhibited significantly more depolarized resting membrane potentials than control cells. We propose cellular alterations in Na+-K+-pump activity and increases in phasic inhibition in MK-801 cells to be the respective underlying mechanisms responsible for the more depolarized resting membrane potentials and the increased power of gamma frequency oscillations observed in MK-801 pretreated animals.
Schizophrenia is a common psychiatric disorder of high incidence, affecting approximately 1% of the world population. The essential neurotransmitter pathology of schizophrenia remains poorly defined, ...despite huge advances over the past half-century in identifying neurochemical and pathological abnormalities in the disease. The dopamine/serotonin hypothesis has originally provided much of the momentum for neurochemical research in schizophrenia. In recent years, the attention has, however, shifted to the glutamate system, the major excitatory neurotransmitter in the CNS and towards a concept of functional imbalance between excitatory and inhibitory transmission at the network level in various brain regions in schizophrenia. The evidence indicating a central role for the NMDA-receptor subtype in the aetiology of schizophrenia has led to the NMDA-hypofunction model of this disease and the use of phencyclidines as a means to induce the NMDA-hypofunction state in animal models. The purpose of this review is to discuss recent findings highlighting the importance of the NMDA-hypofunction model of schizophrenia, both from a clinical perspective, as well as in opening a line of research, which enables electrophysiological studies at the cellular and network level in vitro. In particular, changes in excitation-inhibition (E/I) balance in the NMDA-hypofunction model of the disease and the resulting changes in network behaviours, particularly in gamma frequency oscillatory activity, will be discussed.
GABA(B) receptors (GABA(B)Rs) mediate slow inhibitory effects on neuronal excitability and synaptic transmission in the brain. However, the GABA(B)R agonist baclofen can also promote excitability and ...seizure generation in human patients and animals models. Here we show that baclofen has concentration-dependent effects on the hippocampal network in a mouse model of mesial temporal lobe epilepsy. Application of baclofen at a high dose (10 mg/kg i.p.) reduced the power of γ oscillations and the frequency of pathological discharges in the Cornu Ammonis area 3 (CA3) area of freely moving epileptic mice. Unexpectedly, at a lower dose (1 mg/kg), baclofen markedly increased γ activity accompanied by a higher incidence of pathological discharges. Intracellular recordings from CA3 pyramidal cells in vitro further revealed that, although at a high concentration (10 µM), baclofen invariably resulted in hyperpolarization, at low concentrations (0.5 µM), the drug had divergent effects, producing depolarization and an increase in firing frequency in epileptic but not control mice. These excitatory effects were mediated by the selective muting of inhibitory cholecystokinin-positive basket cells (CCK(+) BCs), through enhanced inhibition of GABA release via presynaptic GABA(B)Rs. We conclude that cell type-specific up-regulation of GABA(B)R-mediated autoinhibition in CCK(+) BCs promotes aberrant high frequency oscillations and hyperexcitability in hippocampal networks of chronic epileptic mice.
Midbrain raphe nuclei provide strong serotonergic projections to the hippocampus, in which serotonin (5-HT) exerts differential effects mediated by multiple 5-HT receptor subtypes. The functional ...relevance of this diversity of information processing is poorly understood. Here we show that serotonin via 5-HT(1B) heteroreceptors substantially reduces synaptic excitation of cholecystokinin-expressing interneurons in area CA1 of the rat hippocampus, in contrast to parvalbumin-expressing basket cells. The reduction is input specific, affecting only glutamatergic synaptic transmission originating from CA1 pyramidal cells. As a result, serotonin selectively decreases feedback inhibition via 5-HT(1B) receptor activation and subsequently increases the integration time window for spike generation in CA1 pyramidal cells. Our data imply an important role for serotonergic modulation of GABAergic action in subcortical control of hippocampal output.
GABA... receptors (GABABRs) mediate slow inhibitory effects on neuronal excitability and synaptic transmission in the brain. However, the GABA...R agonist baclofen can also promote excitability and ...seizure generation in human patients and animals models. Here we show that baclofen has concentration-dependent effects on the hippocampal network in a mouse model of mesial temporal lobe epilepsy. Application of baclofen at a high dose (10 mg/kg i.p.) reduced the power of ... oscillations and the frequency of pathological discharges in the Cornu Ammonis area 3 (CA3) area of freely moving epileptic mice. Unexpectedly, at a lower dose (1 mg/kg), baclofen markedly increased ... activity accompanied by a higher incidence of pathological discharges. Intracellular recordings from CA3 pyramidal cells in vitro further revealed that, although at a high concentration (10 ...M), baclofen invariably resulted in hyperpolarization, at low concentrations (0.5 ...M), the drug had divergent effects, producing depolarization and an increase in firing frequency in epileptic but not control mice. These excitatory effects were mediated by the selective muting of inhibitory cholecystokinin-positive basket cells (CCK+ BCs), through enhanced inhibition of GABA release via presynaptic GABA...Rs. We conclude that cell type-specific up-regulation of GABA...R-mediated autoinhibition in CCK+ BCs promotes aberrant high frequency oscillations and hyperexcitability in hippocampal networks of chronic epileptic mice. (ProQuest: ... denotes formulae/symbols omitted.)
GABAB receptors (GABABRs) mediate slow inhibitory effects on neuronal excitability and synaptic transmission in the brain. However, the GABABR agonist baclofen can also promote excitability and ...seizure generation in human patients and animals models. Here we show that baclofen has concentration-dependent effects on the hippocampal network in a mouse model of mesial temporal lobe epilepsy. Application of baclofen at a high dose (10 mg/kg i.p.) reduced the power of γ oscillations and the frequency of pathological discharges in the Cornu Ammonis area 3 (CA3) area of freely moving epileptic mice. Unexpectedly, at a lower dose (1 mg/kg), baclofen markedly increased γ activity accompanied by a higher incidence of pathological discharges. Intracellular recordings from CA3 pyramidal cells in vitro further revealed that, although at a high concentration (10 µM), baclofen invariably resulted in hyperpolarization, at low concentrations (0.5 µM), the drug had divergent effects, producing depolarization and an increase in firing frequency in epileptic but not control mice. These excitatory effects were mediated by the selective muting of inhibitory cholecystokinin-positive basket cells (CCK⁺ BCs), through enhanced inhibition of GABA release via presynaptic GABABRs. We conclude that cell type-specific up-regulation of GABABR-mediated autoinhibition in CCK⁺ BCs promotes aberrant high frequency oscillations and hyperexcitability in hippocampal networks of chronic epileptic mice.
Significance
Metabotropic GABA
B
receptors control synaptic transmission and excitability in neuronal circuits of the brain. Although effects of these receptors are predominantly inhibitory at both ...cellular and network levels, application of the agonist baclofen can promote excitability and induce seizures in patients and animal models of epilepsy. Here we demonstrate that proepileptic effects of baclofen are concentration dependent and result from disinhibition. Although at high doses, baclofen reduces network excitability due to its combined pre- and postsynaptic inhibitory effects in pyramidal cells, at low doses, it leads to an enhanced presynaptic suppression of the synaptic output of a specific set of inhibitory neurons. This disinhibitory effect promotes high-frequency oscillations and the emergence of pathological discharges in the epileptic hippocampal network.
GABA
B
receptors (GABA
B
Rs) mediate slow inhibitory effects on neuronal excitability and synaptic transmission in the brain. However, the GABA
B
R agonist baclofen can also promote excitability and seizure generation in human patients and animals models. Here we show that baclofen has concentration-dependent effects on the hippocampal network in a mouse model of mesial temporal lobe epilepsy. Application of baclofen at a high dose (10 mg/kg i.p.) reduced the power of γ oscillations and the frequency of pathological discharges in the Cornu Ammonis area 3 (CA3) area of freely moving epileptic mice. Unexpectedly, at a lower dose (1 mg/kg), baclofen markedly increased γ activity accompanied by a higher incidence of pathological discharges. Intracellular recordings from CA3 pyramidal cells in vitro further revealed that, although at a high concentration (10 µM), baclofen invariably resulted in hyperpolarization, at low concentrations (0.5 µM), the drug had divergent effects, producing depolarization and an increase in firing frequency in epileptic but not control mice. These excitatory effects were mediated by the selective muting of inhibitory cholecystokinin-positive basket cells (CCK
+
BCs), through enhanced inhibition of GABA release via presynaptic GABA
B
Rs. We conclude that cell type–specific up-regulation of GABA
B
R-mediated autoinhibition in CCK
+
BCs promotes aberrant high frequency oscillations and hyperexcitability in hippocampal networks of chronic epileptic mice.
GABA... receptors (GABABRs) mediate slow inhibitory effects on neuronal excitability and synaptic transmission in the brain. However, the GABA...R agonist baclofen can also promote excitability and ...seizure generation in human patients and animals models. Here we show that baclofen has concentration-dependent effects on the hippocampal network in a mouse model of mesial temporal lobe epilepsy. Application of baclofen at a high dose (10 mg/kg i.p.) reduced the power of ... oscillations and the frequency of pathological discharges in the Cornu Ammonis area 3 (CA3) area of freely moving epileptic mice. Unexpectedly, at a lower dose (1 mg/kg), baclofen markedly increased ... activity accompanied by a higher incidence of pathological discharges. Intracellular recordings from CA3 pyramidal cells in vitro further revealed that, although at a high concentration (10 ...M), baclofen invariably resulted in hyperpolarization, at low concentrations (0.5 ...M), the drug had divergent effects, producing depolarization and an increase in firing frequency in epileptic but not control mice. These excitatory effects were mediated by the selective muting of inhibitory cholecystokinin-positive basket cells (CCK+ BCs), through enhanced inhibition of GABA release via presynaptic GABA...Rs. We conclude that cell type-specific up-regulation of GABA...R-mediated autoinhibition in CCK+ BCs promotes aberrant high frequency oscillations and hyperexcitability in hippocampal networks of chronic epileptic mice. (ProQuest: ... denotes formulae/symbols omitted.)
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